ABSTRACT
Background: Proton pump inhibitors (PPIs) have been suggested to lead to bone resorption, while the effects of PPIs on the bone mineral metabolism in children has received only limited attention in literature to date. The present study investigates whether lansoprazole alters bone turnover markers in adolescents with gastroesophageal reflux disease (GERD). Patients and methods: Included in the study were adolescents aged 16-18 with GERD and a healthy volunteers group. The GERD patient group was treated with lansoprazole 30 mg once daily for eight weeks. The serum calcium, phosphorus, magnesium, alkaline phosphatase (ALP), parathormone (PTH), 25 (OH) vitamin D, osteocalcin and urinary calcium, creatinine, deoxypyridinoline (DPD), collagen type-1 crosslinked C-telopeptide (CTX) and collagen type-1 crosslinked N-telopeptide (NTX) of both groups were studied before and after the end of the treatment. Results: A comparison of the 30 patients with GERD and the 30 volunteers revealed no significant difference in the serum calcium, phosphorus, magnesium, ALP, urinary calcium/creatinine ratio, 25 (OH) vitamin D and PTH levels measured before and after the lansoprazole treatment, while the osteocalcin, DPD, CTX and NTX values were found to be higher after treatment when compared to those at pre- treatment. Conclusions: The results of this study reveal that eight weeks of treatment with 30 mg lansoprazole daily increased the bone turnover markers of CTX, NTX, DPD and osteocalcin in adolescents aged 16-18.
Subject(s)
Bone Remodeling , Bone Resorption , Gastroesophageal Reflux , Lansoprazole , Proton Pump Inhibitors , Adolescent , Humans , Alkaline Phosphatase/blood , Biomarkers/blood , Bone Remodeling/drug effects , Bone Resorption/chemically induced , Bone Resorption/diagnosis , Calcium/blood , Creatinine/blood , Gastroesophageal Reflux/drug therapy , Lansoprazole/adverse effects , Lansoprazole/therapeutic use , Magnesium/blood , Osteocalcin/blood , Parathyroid Hormone/blood , Peptides/blood , Phosphorus/blood , Proton Pump Inhibitors/adverse effects , Proton Pump Inhibitors/therapeutic use , Vitamin D/bloodABSTRACT
There is an increasing incidence of destructive bone disease caused by osteoclast proliferation. This is characterized by reduced bone mass and imbalance of bone homeostasis. Icariin (ICA), a flavonoid compound isolated from Epimedium, has antiosteoporosis activity and inhibits the formation of osteoclasts and bone resorption. The purpose of the present study was to investigate the protective effect of ICA on osteoclastic differentiation induced by thioacetamide (TAA) and its possible mechanism in Sprague Dawley (SD) rats. In the present study, SD rats were intraperitoneally injected with TAA (300 mg/kg) for the bone loss model, treated with ICA (600 mg/kg, intragastric gavage) in the ICA group and TAA+ICA group for treatment of bone loss for 6 weeks. Indexes associated with bone metabolism, such as alkaline phosphatase, Nterminal telopeptide of typeI collagen (NTXI), calcium (Ca), phosphorus (P) and magnesium (Mg) in the serum, were detected. Osteoclast differentiation of femoral tissues was detected by hematoxylin and eosin and tartrateresistant acid phosphatase staining. The femoral bone mass was evaluated using a threepoint bending test and micro computed tomography. Western blotting was used to detect the expression levels of osteoclastrelated proteins in each group. In the rats treated with TAA, the serum concentrations of Ca, P and Mg were decreased, the serum concentration of NTXI was increased, osteoclast differentiation of the femur was increased, femur bone stress and bone mass were decreased and the bone loss and osteoclast formation were reduced after ICA treatment. In addition, ICA inhibited the protein expression of receptor activator of nuclear factor κΒ ligand (RANKL), receptor activator of nuclear factor κB (RANK), p38, ERK, cFos and nuclear factor of activated T cells 1 (NFATc1) in the femur of rats treated with TAA. The results suggested that ICA may inhibit osteoclast differentiation by downregulating the RANKLp38/ERKNFAT signaling pathway and prevent TAAinduced bone loss. The results are helpful to understand the mechanism of osteoclast differentiation induced by TAA, as well as the antiresorptive activity and molecular mechanism of ICA, and to provide new ideas for the treatment of osteolytic diseases.
Subject(s)
Bone Resorption/drug therapy , Bone Resorption/metabolism , Flavonoids/pharmacology , Protective Agents/pharmacology , RANK Ligand/metabolism , Transcription Factors/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism , Alkaline Phosphatase/blood , Animals , Body Weight/drug effects , Bone Resorption/chemically induced , Calcium/blood , Cell Differentiation/drug effects , Collagen Type I/blood , Disease Models, Animal , Femur/diagnostic imaging , Femur/drug effects , Femur/metabolism , Flavonoids/therapeutic use , MAP Kinase Signaling System/drug effects , Magnesium/blood , Male , Osteoclasts/drug effects , Peptides/blood , Phosphorus/blood , Protective Agents/therapeutic use , Rats, Sprague-Dawley , Thioacetamide/toxicity , X-Ray MicrotomographyABSTRACT
Osteoporosis is a chronic disease that has become a serious public health problem due to the associated reduction in quality of life and its increasing financial burden. It is known that inhibiting osteoclast differentiation and promoting osteoblast formation prevents osteoporosis. As there is no drug with this dual activity without clinical side effects, new alternatives are needed. Here, we demonstrate that austalide K, isolated from the marine fungus Penicillium rudallenes, has dual activities in bone remodeling. Austalide K inhibits the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and improves bone morphogenetic protein (BMP)-2-mediated osteoblast differentiation in vitro without cytotoxicity. The nuclear factor of activated T cells c1 (NFATc1), tartrate-resistant acid phosphatase (TRAP), dendritic cell-specific transmembrane protein (DC-STAMP), and cathepsin K (CTSK) osteoclast-formation-related genes were reduced and alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and osteopontin (OPN) (osteoblast activation-related genes) were simultaneously upregulated by treatment with austalide K. Furthermore, austalide K showed good efficacy in an LPS-induced bone loss in vivo model. Bone volume, trabecular separation, trabecular thickness, and bone mineral density were recovered by austalide K. On the basis of these results, austalide K may lead to new drug treatments for bone diseases such as osteoporosis.
Subject(s)
Bone Density Conservation Agents/therapeutic use , Bone Resorption/prevention & control , Osteoblasts/drug effects , Osteoclasts/drug effects , Penicillium/chemistry , Xanthenes/therapeutic use , Animals , Bone Density Conservation Agents/isolation & purification , Bone Density Conservation Agents/pharmacology , Bone Resorption/chemically induced , Cell Differentiation/drug effects , Disease Models, Animal , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Geologic Sediments/microbiology , Lipopolysaccharides/toxicity , Male , Mice , Mice, Inbred ICR , Molecular Structure , NFATC Transcription Factors/biosynthesis , NFATC Transcription Factors/genetics , Osteoporosis , Penicillium/isolation & purification , RANK Ligand/pharmacology , Tartrate-Resistant Acid Phosphatase/antagonists & inhibitors , Xanthenes/isolation & purification , Xanthenes/pharmacologyABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Plastrum testudinis (PT) is a kind of single traditional Chinese medicine that can tonify kidney and strengthen bone. Plastrum testudinis extract (PTE) has been approved to promote the osteogenic differentiation of bone marrow-derived mesenchymal stem cells in vitro. However, the mechanism by which PTE reduces osteoclast differentiation has not yet been reported. AIM OF THE STUDY: To explore the potential of PTE as a therapeutic treatment for bone loss caused by senile osteoporosis (SOP). MATERIALS AND METHODS: We evaluated whether PTE could inhibit RANKL-induced osteoclast differentiation both in vitro and in vivo, and investigated PTE-induced phenotypes of human peripheral blood monocytes. RESULTS: We found that PTE inhibited osteoclast differentiation and bone resorption in vitro in a concentration-dependent manner and that PTE treatment is most effective during the early stages of osteoclastogenesis. Moreover, we found that PTE could block the NF-κB signaling pathway in vitro, leading to the down-regulation of osteoclast-specific genes including C-FOS and NFATC1. The results from our in vivo mouse study suggest that PTE treatment suppresses osteoclast formation and mitigates bone loss caused by SOP. Notably, we also found that PTE inhibited RANKL-induced osteoclast differentiation in human peripheral blood monocytes. CONCLUSION: Our results suggest that PTE treatment suppresses osteoclastogenesis and ameliorates bone loss caused by SOP by selectively blocking the nuclear translocation of NF-κB/p50.
Subject(s)
Cell Differentiation/drug effects , NF-kappa B/metabolism , Osteoclasts/drug effects , Osteoporosis/drug therapy , Signal Transduction/drug effects , Tissue Extracts/pharmacology , Animals , Bone Resorption/chemically induced , Bone Resorption/drug therapy , Bone Resorption/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Humans , Lipopolysaccharides/toxicity , Male , Mice, Inbred C57BL , NF-kappa B p50 Subunit/metabolism , NFATC Transcription Factors/metabolism , Osteoclasts/cytology , Osteoclasts/metabolism , Osteogenesis/drug effects , Osteoporosis/etiology , Osteoporosis/metabolism , RANK Ligand/toxicity , Tissue Extracts/therapeutic useABSTRACT
Octanoic acid is a medium-chained saturated fatty acid found abundantly in the ketogenic dietary supplements containing medium chained triglycerides (MCT) along with decanoic acid. The MCT ketogenic diet is commonly consumed for weight loss but has also showcased neuroprotective potential against neurodegenerative disorders. However, recent clinical findings have reported a critical disadvantage with the long-term consumption of ketogenic diet i.e. bone loss. The following study was employed to investigate whether the two major components of MCT diet also possess bone loss potential as observed with classical ketogenic diet. Swiss albino mice aged between 10 and 12 weeks, were divided into 3 treatment groups that were administered with oral suspensions of octanoic acid, decanoic acid and a combination of both for 4 weeks. Bone specific markers, microarchitectural parameters, using micro computed tomography, and biomechanical strength were analyzed. Remarkably deleterious alterations in the trabecular bone microarchitecture, and on bone markers were observed in the octanoic acid treated groups. Our results suggest significant negative effects on bone health by octanoic acid. These findings require further investigation and validation in order to provide significant clinically relevant data to possibly modify dietary composition of the MCT ketogenic diet.
Subject(s)
Bone Resorption/chemically induced , Cancellous Bone/physiopathology , Caprylates/adverse effects , Decanoic Acids/pharmacology , Diet, Ketogenic/adverse effects , Dietary Supplements/adverse effects , Animals , Biomechanical Phenomena/drug effects , Bone Density/drug effects , Diet, High-Protein Low-Carbohydrate/adverse effects , Femur/physiopathology , Ketone Bodies/urine , Male , Mice , Neuroprotective Agents/adverse effects , Osteoclasts/drug effects , Random Allocation , Tibia/physiopathology , Triglycerides/administration & dosageABSTRACT
Dietary procyanidin has been shown to be an important bioactive component that regulates various pharmacological activities to maintain metabolic homeostasis. In particular, grape seed proanthocyanidin extract (GSPE) is a commercially available medicine for the treatment of venous and lymphatic dysfunction. This study aimed to investigate whether GSPE protects against lipopolysaccharide (LPS)-induced bone loss in vivo and the related mechanism of action in vitro. The administration of GSPE restored the inflammatory bone loss phenotype stimulated by acute systemic injection of LPS in vivo. GSPE strongly suppressed receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclast differentiation and bone resorption activity of mature osteoclasts by decreasing the RANKL-induced nuclear factor-κB transcription activity. GSPE mediates this effect through decreased phosphorylation and degradation of NF-κB inhibitor (IκB) by IκB kinaseß, subsequently inhibiting proto-oncogene cellular Fos and nuclear factor of activated T cells. Additionally, GSPE promotes osteoclast proliferation by increasing the phosphorylation of components of the Akt and mitogen-activated protein kinase signaling pathways and it also inhibits apoptosis by decreasing the activity of caspase-8, caspase-9, and caspase-3, as corroborated by a decrease in the Terminal deoxynucleotidyl transferase dUTP nick end labeling -positive cells. Our study suggests a direct effect of GSPE on the proliferation, differentiation, and apoptosis of osteoclasts and reveals the mechanism responsible for the therapeutic potential of GSPE in osteoclast-associated bone metabolism disease.
Subject(s)
Apoptosis/drug effects , Bone Resorption/pathology , Bone Resorption/prevention & control , Cell Differentiation/drug effects , Cell Proliferation/drug effects , Grape Seed Extract/administration & dosage , Grape Seed Extract/pharmacology , Osteoclasts/physiology , Osteogenesis/drug effects , Proanthocyanidins/administration & dosage , Proanthocyanidins/pharmacology , Animals , Bone Marrow Cells/cytology , Bone Resorption/chemically induced , Bone Resorption/physiopathology , Cells, Cultured , Lipopolysaccharides/adverse effects , Male , Mice, Inbred ICR , NF-kappa B/metabolism , Osteoclasts/pathology , RANK Ligand/metabolismABSTRACT
PURPOSE: Prolonged use of proton pump inhibitors may cause bone loss, and limited therapeutic agents are available to prevent this skeletal side effect. The combination of annatto tocotrienol, a bone anabolic agent, with calcium presents a novel strategy to prevent bone loss caused by proton pump inhibitors. This study aims to compare the effects of calcium alone and in combination with annatto tocotrienol or vitamin D3 (Caltrate Plus) in preventing bone loss caused by pantoprazole. METHODS: Three-month-old Sprague Dawley male rats (n=30) were randomised into five groups (n=6/group). Bone loss was induced by pantoprazole (3 mg/kg p.o.) in four groups, and they were treated concurrently with either calcium carbonate (77 mg p.o.), calcium carbonate (77 mg p.o.) plus annatto tocotrienol (60 mg/kg p.o.) or Caltrate Plus (31 mg p.o.) for 60 days. The rats were euthanised at the end of the experiment, and their femurs were harvested for X-ray micro-computed tomography, bone cellular histomorphometry and bone mechanical strength analysis. RESULTS: Pantoprazole caused significant deterioration of trabecular bone microstructures but did not affect other skeletal indices. Calcium supplementation with or without annatto tocotrienol prevented the deterioration of trabecular microstructures at the femur but did not improve other skeletal indices. Annatto tocotrienol did not enhance the skeletal actions of calcium, whereas Caltrate Plus did not affect the bone health indices in these rats. CONCLUSION: Calcium supplementation per se can prevent the deterioration of bone trabecular microstructures in rats receiving long-term treatment of pantoprazole.
Subject(s)
Bone Resorption/drug therapy , Bone and Bones/drug effects , Calcium/pharmacology , Tocotrienols/pharmacology , Animals , Bone Density/drug effects , Bone Resorption/chemically induced , Calcium/administration & dosage , Dietary Supplements , Male , Rats , Rats, Sprague-Dawley , Tocotrienols/administration & dosageABSTRACT
Early-stage breast cancer (BC) patients receiving adjuvant therapy suffer from bone loss and increased fracture risk. Zoledronic acid (ZA) has been confirmed to inhibit bone metastasis and improve survival outcomes in early BC postmenopausal patients receiving adjuvant therapy. However, the efficacy of ZA for prevention of adjuvant therapy-induced bone loss from 2 different early BC groups, namely premenopausal and postmenopausal patients, still remain unclear. To obtain detailed characteristics, we performed this meta-analysis. PubMed, EMBASE, and Cochrane were searched. In premenopausal BC patients and postmenopausal BC patients, to assess bone loss, we calculated the weighted mean differences with 95% confidence intervals (CI) to evaluate lumbar spine (LS) bone mineral density (BMD), total hip (TH) BMD, and femoral neck (FN) BMD in ZA and non-ZA group with follow-up of 12 months. Thirteen randomized controlled trials (RCTs) encompassing 7375 patients were included. In a mixed population of early BC patients receiving adjuvant therapy, ZA significantly increased LS BMD (P < 0.00001), TH BMD (P < 0.00001), and FN BMD (Pâ¯=â¯0.01) compared with non-ZA group. In premenopausal patient subgroup, LS BMD was greatly higher in patients with ZA compared to controls (0.06 g/cm2; 95% CI: 0.05-0.08), whereas there were no differences in TH BMD and FN BMD between patients with ZA and controls. In postmenopausal patient subgroup, both LS BMD (0.06 g/cm2; 95% CI: 0.05-0.07) and TH BMD (0.04 g/cm2; 95% CI: 0.03-0.04) were significantly higher in patients with ZA compared to controls, but there was no difference in FN BMD between patients with ZA and controls. To sum up, ZA prevents bone loss in early-stage BC patients receiving adjuvant therapy at different skeletal sites. In premenopausal patients, effectiveness of ZA in prevention of bone loss is confirmed at LS site, but not at TH and FN site. In postmenopausal patients, ZA has a satisfying efficacy for prevention of bone loss at LS and TH site, but not at FN site.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bone Density Conservation Agents/therapeutic use , Bone Resorption/prevention & control , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant/adverse effects , Zoledronic Acid/therapeutic use , Bone Resorption/chemically induced , Bone Resorption/pathology , Breast Neoplasms/pathology , Female , Humans , Prognosis , Randomized Controlled Trials as TopicABSTRACT
Kavain, a compound derived from Piper methysticum, has demonstrated anti-inflammatory properties. To optimize its drug properties, identification and development of new kavain-derived compounds was undertaken. A focused library of analogs was synthesized and their effects on Porphyromonas gingivalis (P. gingivalis) elicited inflammation were evaluated in vitro and in vivo. The library contained cyclohexenones (5,5-dimethyl substituted cyclohexenones) substituted with a benzoate derivative at the 3-position of the cyclohexanone. The most promising analog identifed was a methylated derivative of kavain, Kava-205Me (5,5-dimethyl-3-oxocyclohex-1-en-1-yl 4-methylbenzoate.) In an in vitro assay of anti-inflammatory effects, murine macrophages (BMM) and THP-1 cells were infected with P. gingivalis (MOI = 20:1) and a panel of cytokines were measured. Both cell types treated with Kava-205Me (10 to 200 µg/ml) showed significantly and dose-dependently reduced TNF-α secretion induced by P. gingivalis. In BMM, Kava-205Me also reduced secretion of other cytokines involved in the early phase of inflammation, including IL-12, eotaxin, RANTES, IL-10 and interferon-γ (p < 0.05). In vivo, in an acute model of P. gingivalis-induced calvarial destruction, administration of Kava-205Me significantly improved the rate of healing associated with reduced soft tissue inflammation and osteoclast activation. In an infective arthritis murine model induced by injection of collagen-antibody (ArthriomAb) + P. gingivalis, administration of Kava-205Me was able to reduce efficiently paw swelling and joint destruction. These results highlight the strong anti-inflammatory properties of Kava-205Me and strengthen the interest of testing such compounds in the management of P. gingivalis elicited inflammation, especially in the management of periodontitis.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Bone Resorption/drug therapy , Inflammation/drug therapy , Kava/chemistry , Plant Extracts/pharmacology , Skull/drug effects , Animals , Arthritis, Experimental/chemically induced , Bone Resorption/chemically induced , Bone Resorption/pathology , Cytokines/metabolism , Inflammation/chemically induced , Inflammation/pathology , Lipopolysaccharides/toxicity , Macrophages/drug effects , Macrophages/pathology , Male , Mice , Mice, Inbred DBA , Porphyromonas gingivalis/isolation & purification , Skull/pathologyABSTRACT
Bone resorption, initiated by osteoclasts (OCs), plays an essential role in bone homeostasis. The abnormalities of bone resorption may induce a series of diseases, including osteoarthritis, osteoporosis and aseptic peri-implant loosening. Nirogacestat (PF-03084014, PF), a novel gamma-secretase inhibitor, has been used in phase II clinical trial for treatment of desmoid tumor. However, whether it has the therapeutic effect on abnormal bone resorption remains to be evaluated. In this study, we investigated the role of PF in the regulation of receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclastogenesis in vitro, and the lipopolysaccharide (LPS)-induced bone resorption in vivo. It was found that PF could suppress the formation of osteoclasts from bone marrow macrophages (BMMs) without causing cytotoxicity, inhibit bone resorption and downregulate the mRNA level of osteoclast-specific markers, including calcitonin receptor (CTR), tartrate resistant acid phosphatase (TRAP), cathepsin K (CTSK), dendritic cell-specific transmembrane protein (Dc-stamp), Atp6v0d2 (V-ATPase d2) and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1). Furthermore, Notch2 signaling, as well as RANKL-induced AKT signaling was significantly inhibited in BMMs. Consistent with in vitro observation, we found that PF greatly ameliorated LPS-induced bone resorption. Taken together, our study demonstrated that PF has a great potential to be used in management of osteolytic diseases.
Subject(s)
Bone Resorption/drug therapy , Macrophages/drug effects , Osteoclasts/drug effects , Osteogenesis/drug effects , Tetrahydronaphthalenes/therapeutic use , Valine/analogs & derivatives , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Animals , Bone Resorption/chemically induced , Cells, Cultured , Drug Evaluation, Preclinical , Lipopolysaccharides/toxicity , Macrophage Colony-Stimulating Factor/pharmacology , Male , Mice , Mice, Inbred C57BL , Osteolysis/chemically induced , Osteolysis/drug therapy , RANK Ligand/pharmacology , Recombinant Proteins/pharmacology , Tetrahydronaphthalenes/pharmacology , Valine/pharmacology , Valine/therapeutic useABSTRACT
Antibiotic treatment, commonly prescribed for bacterial infections, depletes and subsequently causes long-term alterations in intestinal microbiota composition. Knowing the importance of the microbiome in the regulation of bone density, we investigated the effect of postantibiotic treatment on gut and bone health. Intestinal microbiome repopulation at 4-weeks postantibiotic treatment resulted in an increase in the Firmicutes:Bacteroidetes ratio, increased intestinal permeability, and notably reduced femoral trabecular bone volume (approximately 30%, p < 0.01). Treatment with a mucus supplement (a high-molecular-weight polymer, MDY-1001 [MDY]) prevented the postantibiotic-induced barrier break as well as bone loss, indicating a mechanistic link between increased intestinal permeability and bone loss. A link between the microbiome composition and bone density was demonstrated by supplementing the mice with probiotic bacteria. Specifically, Lactobacillus reuteri, but not Lactobacillus rhamnosus GG or nonpathogenic Escherichia coli, reduced the postantibiotic elevation of the Firmicutes:Bacteroidetes ratio and prevented femoral and vertebral trabecular bone loss. Consistent with causing bone loss, postantibiotic-induced dysbiosis decreased osteoblast and increased osteoclast activities, changes that were prevented by both L. reuteri and MDY. These data underscore the importance of microbial dysbiosis in the regulation of intestinal permeability and bone health, as well as identify L. reuteri and MDY as novel therapies for preventing these adverse effects. © 2018 American Society for Bone and Mineral Research.
Subject(s)
Anti-Bacterial Agents/adverse effects , Bone Resorption , Dysbiosis , Gastrointestinal Microbiome/drug effects , Limosilactobacillus reuteri , Probiotics/pharmacology , Animals , Anti-Bacterial Agents/pharmacology , Bacteroides/classification , Bacteroides/growth & development , Bone Resorption/chemically induced , Bone Resorption/microbiology , Bone Resorption/pathology , Bone Resorption/prevention & control , Dysbiosis/chemically induced , Dysbiosis/microbiology , Dysbiosis/prevention & control , Firmicutes/classification , Firmicutes/growth & development , Male , Mice , Mice, Inbred BALB CABSTRACT
BACKGROUND: Aromatase inhibitors (AI) have been established as the gold-standard therapy for postmenopausal patients. Worldwide, adjuvant denosumab at a dose of 60 mg twice per year reduces the risk of clinical fractures in postmenopausal patients with breast cancer who received AI. However, the efficacy of denosumab in the treatment of AI-associated bone loss had not been prospectively evaluated in Japan. Previously, we reported the 12-month effect of denosumab in Japanese patients for the first time; the primary endpoint was the change in the percentage of bone mineral density (BMD) of the lumbar spine from baseline to 12 months. METHODS: This secondary follow-up study prospectively evaluated the change in the percentage of BMD of the lumbar spine from baseline to 24 months. Postmenopausal women with early-stage, histologically confirmed, hormone receptor-positive, invasive breast cancer who were receiving or scheduled to receive AI were included. Denosumab was administered subcutaneously on day 1 of the study and then 6, 12, 18, and 24 months. The lumbar spine and bilateral femoral neck BMD was measured at baseline and 6, 12, 18, and 24 months. RESULTS: At 18 and 24 months, the lumbar spine BMD increased by 5.9 and 7.0%, respectively. The femoral neck BMD also increased. Grade ≥ 2 hypocalcemia, osteonecrosis of the jaw, and atypical femoral fractures did not occur. CONCLUSIONS: Our prospective study showed that semiannual treatment with denosumab was associated with continuously increased BMD in Japanese women receiving adjuvant AI therapy for up to 24 months, regardless of prior AI treatment.
Subject(s)
Antineoplastic Agents, Hormonal/adverse effects , Aromatase Inhibitors/adverse effects , Bone Density Conservation Agents/pharmacology , Bone Resorption/drug therapy , Breast Neoplasms/therapy , Denosumab/pharmacology , Absorptiometry, Photon , Aged , Bone Density/drug effects , Bone Density Conservation Agents/therapeutic use , Bone Resorption/chemically induced , Bone Resorption/diagnostic imaging , Chemotherapy, Adjuvant/adverse effects , Chemotherapy, Adjuvant/methods , Denosumab/therapeutic use , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Injections, Subcutaneous , Japan , Lumbar Vertebrae/diagnostic imaging , Middle Aged , Postmenopause , Prospective Studies , Treatment OutcomeABSTRACT
PURPOSE: Premenopausal women receiving chemotherapy or endocrine treatment for early breast cancer are at increased risk for cancer treatment induced bone loss (CTIBL). The aim of the randomized, double-blind ProBONE II trial was to investigate whether a 2-year adjuvant treatment with 4â¯mg intravenous zoledronic acid (ZOL) every 3â¯months versus placebo would prevent CTIBL after a five-year period. METHODS: Thirty-one of the 34 participants in the ZOL arm and thirty-four of the 36 participants in the placebo arm were followed-up to the 5-year visit and completed the study as planned. The changes in Bone Mass Density (BMD) were assessed at baseline and each visit after treatment initiation. RESULTS: After 24â¯months, BMD at the lumbar spine showed a 2.9% increase in patients treated with ZOL vs. a 7.1% decrease in placebo-treated participants compared to baseline (pâ¯<â¯0.001). Over the 60-month study period, we found a decrease of 2.2% vs. 7.3% in the BMD at the lumbar spine in patients receiving ZOL and placebo respectively (pâ¯<â¯0.001). Over the 60-month study period, BMD in the placebo arm showed a continuous decrease at all sites (pâ¯<â¯0001), whereas patients treated with ZOL reached baseline BMD-values at the femoral neck and total hip. CONCLUSIONS: In ProBone II, a 2-year treatment with ZOL 4â¯mg intravenous every 3â¯months prevented cancer treatment induced bone loss in premenopausal women with breast cancer and maintained the BMD up to 3â¯years post-treatment.
Subject(s)
Antineoplastic Agents/adverse effects , Bone Density Conservation Agents/administration & dosage , Bone Resorption/prevention & control , Breast Neoplasms/drug therapy , Premenopause/drug effects , Zoledronic Acid/administration & dosage , Administration, Intravenous , Adult , Antineoplastic Agents/administration & dosage , Bone Resorption/chemically induced , Bone Resorption/diagnostic imaging , Bone Resorption/epidemiology , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/epidemiology , Double-Blind Method , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Middle Aged , Premenopause/physiology , Prospective Studies , Time Factors , Treatment Outcome , Young AdultABSTRACT
To better understand the association between high salt intake and osteoporosis, we investigated the effect of sodium chloride (NaCl) on mice and human osteoclastogenesis. The results suggest a direct, activating role of NaCl supplementation on bone resorption. INTRODUCTION: High NaCl intake is associated with increased urinary calcium elimination and parathyroid hormone (PTH) secretion which in turn stimulates the release of calcium from the bone, resulting in increased bone resorption. However, while calciuria after NaCl loading could be shown repeatedly, several studies failed to reveal a significant increase in PTH in response to a high-sodium diet. Another possible explanation that we investigated here could be a direct effect of high-sodium concentration on bone resorption. METHODS: Mouse bone marrow macrophage and human peripheral blood mononuclear cells (PBMC) driven towards an osteoclastogenesis pathway were cultivated under culture conditions mimicking hypernatremia environments. RESULTS: In this study, a direct effect of increased NaCl concentrations on mouse osteoclast differentiation and function was observed. Surprisingly, in a human osteoclast culture system, significant increases in the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts, calcitonin receptor (CTR)-positive osteoclasts, nuclear factor-activated T cells c1 (NFATc1) gene expression, and areal and volumetric resorptions were observed for increasing concentrations of NaCl. This suggests a direct, activating, cell-mediated effect of increased concentrations of NaCl on osteoclasts. CONCLUSIONS: The reported that enhanced bone resorption after high-sodium diets may not only be secondary to the urinary calcium loss but may also be a direct, cell-mediated effect on osteoclastic resorption. These findings allow us to suggest an explanation for the clinical findings independent of a PTH-mediated regulation.
Subject(s)
Osteoclasts/drug effects , Osteogenesis/drug effects , Sodium Chloride/pharmacology , Animals , Bone Resorption/chemically induced , Bone Resorption/metabolism , Bone Resorption/physiopathology , Cell Differentiation/drug effects , Cells, Cultured , Dose-Response Relationship, Drug , Humans , Mice , Osteoclasts/cytology , Osteoclasts/metabolism , Receptors, Calcitonin/metabolism , Sodium Chloride/administration & dosage , Tartrate-Resistant Acid Phosphatase/metabolismABSTRACT
Experimental autoimmune myasthenia gravis (EAMG), an animal model of myasthenia gravis (MG), can be induced in C57BL/6 (B6, H-2 b) mice by 2-3 injections with Torpedo californica AChR (tAChR) in complete Freund's adjuvant. Some EAMG mice exhibit weight loss with muscle weakness. The loss in body weight, which is closely associated with bone structure, is particularly evident in EAMG mice with severe muscle weakness. However, the relationship between muscle weakness and bone loss in EAMG has not been studied before. Recent investigations on bone have shed light on association of bone health and immunological states. It is possible that muscle weakness in EAMG developed by anti-tAChR immune responses might accompany bone loss. We determined whether reduced muscle strength associates with decreased bone mineral density (BMD) in EAMG mice. EAMG was induced by two injections at 4-week interval of tAChR and adjuvants in two different age groups. The first tAChR injection was either at age 8 weeks or at 15 weeks. We measured BMD at three skeletal sites, including femur, tibia, and lumbar vertebrae, using dual energy X-ray absorptiometry. Among these bone areas, femur of EAMG mice in both age groups showed a significant decrease in BMD compared to control adjuvant-injected and to non-immunized mice. Reduction in BMD in induced EAMG at a later-age appears to parallel the severity of the disease. The results indicate that anti-tAChR autoimmune response alone can reduce bone density in EAMG mice. BMD reduction was also observed in adjuvant-injected mice in comparison to normal un-injected mice, suggesting that BMD decrease can occur even when muscle activity is normal. Decreased BMD observed in both tAChR-injected and adjuvant-injected mice groups were discussed in relation to innate immunity and bone-related immunology involving activated T cells and tumour necrosis factor-related cytokines that trigger osteoclastogenesis and bone loss.
Subject(s)
Bone Density/immunology , Bone Resorption/pathology , Muscle Weakness/pathology , Myasthenia Gravis, Autoimmune, Experimental/pathology , Absorptiometry, Photon , Age Factors , Animals , Bone Resorption/chemically induced , Bone Resorption/diagnostic imaging , Bone Resorption/immunology , Femur/diagnostic imaging , Femur/immunology , Femur/pathology , Fish Proteins/administration & dosage , Freund's Adjuvant/administration & dosage , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/immunology , Lumbar Vertebrae/pathology , Male , Mice , Mice, Inbred C57BL , Muscle Weakness/chemically induced , Muscle Weakness/diagnostic imaging , Muscle Weakness/immunology , Myasthenia Gravis, Autoimmune, Experimental/chemically induced , Myasthenia Gravis, Autoimmune, Experimental/diagnostic imaging , Myasthenia Gravis, Autoimmune, Experimental/metabolism , Receptors, Cholinergic/administration & dosage , Severity of Illness Index , Tibia/diagnostic imaging , Tibia/immunology , Tibia/pathology , Time Factors , Torpedo/metabolismABSTRACT
Intensive cancer chemotherapy causes significant bone loss, for which the mechanisms remain unclear and effective treatments are lacking. This is a significant issue particularly for childhood cancers, as the most common ones have a >75% cure rate following chemotherapy; there is an increasing population of survivors who live with chronic bone defects. Studies suggest that these defects are the result of reduced bone from increased marrow fat formation and increased bone resorption following chemotherapy. These changes probably result from altered expression/activation of regulatory molecules or pathways regulating skeletal cell formation and activity. Treatment with methotrexate, an antimetabolite commonly used in childhood oncology, has been shown to increase levels of proinflammatory/pro-osteoclastogenic cytokines (e.g., enhanced NF-κB activation), leading to increased osteoclast formation and bone resorption, as well as to attenuate Wnt signaling, leading to both decreased bone and increased marrow fat formation. In recent years, understanding the mechanisms of action and potential health benefits of selected nutraceuticals, including resveratrol, genistein, icariin, and inflammatory fatty acids, has led to preclinical studies that, in some cases, indicate efficacy in reducing chemotherapy-induced bone defects. We summarize the supporting evidence.
Subject(s)
Antimetabolites, Antineoplastic/adverse effects , Bone Resorption/chemically induced , Bone Resorption/prevention & control , Dietary Supplements , Methotrexate/adverse effects , Neoplasms/drug therapy , Protective Agents/therapeutic use , Stilbenes/therapeutic use , Antimetabolites, Antineoplastic/therapeutic use , Cell Differentiation/drug effects , Child , Humans , Methotrexate/therapeutic use , ResveratrolABSTRACT
Aseptic prosthetic loosening is a major complication after hip joint replacement. Wear particle-induced periprosthetic osteolysis plays a key role in aseptic prosthetic loosening. Attempting to modulate receptor activator of nuclear factor-κB (RANKL) mediated signaling pathways is a promising strategy to prevent aseptic prosthetic loosening. In the present study, we determined the effect of scutellarin (SCU) on titanium (Ti) particle-induced osteolysis in a mouse calvarial model and RANKL-mediated osteoclastogenesis. We determined that SCU, the major effective constituent of breviscapine isolated from a Chinese herb, has potential effects on preventing Ti particle-caused osteolysis in calvarial model of mouse. In vitro, SCU could suppress RANKL-mediated osteoclastogenesis, the function of osteoclast bone resorption, and the expression levels of osteoclast-specific genes (tartrate-resistant acid phosphatase (TRAP), cathepsin K, c-Fos, NFATc1). Further investigation indicated that SCU could inhibit RANKL-mediated MAPK and NF-κB signaling pathway, including JNK1/2, p38, ERK1/2, and IκBα phosphorylation. Taken together, these results indicate that SCU could inhibit osteoclastogenesis and prevent Ti particle-induced osteolysis by suppressing RANKL-mediated MAPK and NF-κB signaling pathway. These results suggest that SCU is a promising therapeutic agent for preventing wear particle-induced periprosthetic osteolysis.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Apigenin/pharmacology , Bone Resorption/drug therapy , Drugs, Chinese Herbal/therapeutic use , Glucuronates/pharmacology , Macrophages/drug effects , Osteoclasts/drug effects , Osteolysis/drug therapy , Prosthesis Failure/drug effects , Animals , Bone Resorption/chemically induced , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , Macrophages/physiology , Male , Mice , Mice, Inbred C57BL , Microspheres , NF-kappa B/metabolism , Osteoclasts/physiology , Osteolysis/chemically induced , RANK Ligand/metabolism , RAW 264.7 Cells , Signal Transduction/drug effects , TitaniumABSTRACT
The present study was performed in order to examine bone loss and calcium homeostasis in mice with glucocorticoid (GC)-induced osteoporosis (GIOP) following treatment with the aqueous extract of pomegranate seed (AE-PS). In addition, a comparative study with alendronate was performed. Biomarkers in the serum and the urine were measured. The tibias, kidney and duodenum were removed in order to measure the levels of bone calcium, protein expression as well as to perform histomorphological analysis of the bone. GC treatment facilitated the induction of hypercalciuria in the mice, and the AE-PStreated mice exhibited a greater increase in serum calcium and a decrease in urine calcium. The AE-PS reversed the deleterious effects on the trabecular bone induced by DXM and stimulated bone remodeling, including an increase in bone calcium and alkaline phosphataseb (ALP-b) and a decrease in a the critical bone resorption markers C-terminal telopeptide of type I collagen (CTX) and tartrateresistant acid phosphatase-5b (TRAP-5b). Hematoxylin and eosin (H&E) staining revealed the increased disconnections and separation between the growth plate and the trabecular bone network as well as the reduction in the trabecular bone mass of the primary and secondary spongiosa throughout the proximal metaphysis of the tibia in the DXM group. Moreover, the decreased protein expression of transient receptor potential vanilloid (TRPV)5, TRPV6 and calbindinD9k (CaBP9k) was reversed by the AE-PS or alendronate supplementation in the kidneys and the duodenum as well as plasma membrane Ca2+ATPase1 (PMCA1) expression in the kidneys of mice with GIOP. There was no marked difference in pharmacological effectiveness between alendronate and the AE-PS. Taken together, these findings suggest that the AE-PS may be an alternative therapy suitable for use in the management of secondary osteoporosis.
Subject(s)
Alendronate/therapeutic use , Bone Resorption/drug therapy , Glucocorticoids/adverse effects , Hypercalciuria/drug therapy , Lythraceae/chemistry , Plant Extracts/therapeutic use , Seeds/chemistry , Water/chemistry , Animals , Bone Resorption/chemically induced , Bone Resorption/complications , Bone Resorption/pathology , Calcium/blood , Calcium/urine , Duodenum/drug effects , Duodenum/metabolism , Duodenum/pathology , Hypercalciuria/blood , Hypercalciuria/chemically induced , Hypercalciuria/complications , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Male , Membrane Transport Proteins/metabolism , Mice, Inbred C57BL , Osteoprotegerin/metabolism , Phytotherapy , Plant Extracts/pharmacology , RANK Ligand/metabolism , Receptors, Calcium-Sensing/metabolism , Tartrate-Resistant Acid Phosphatase/metabolism , Testosterone/blood , Tibia/drug effects , Tibia/metabolism , Tibia/pathologyABSTRACT
Dendrobium moniliforme (DM) is a well-known plant-derived extract that is widely used in Oriental medicine. DM and its chemical constituents have been reported to have a variety of pharmacological effects, including anti-oxidative, anti-inflammatory, and anti-tumor activities; however, no reports discuss the beneficial effects of DM on bone diseases such as osteoporosis. Thus, we investigated the relationship between DM and osteoclasts, cells that function in bone resorption. We found that DM significantly reduced receptor activator of nuclear factor kappa-B ligand (RANKL)-induced tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation; DM directly induced the down-regulation of c-Fos and nuclear factor of activated T cells c1 (NFATc1) without affecting other RANKL-dependent transduction pathways. In the later stages of osteoclast maturation, DM negatively regulated the organization of filamentous actin (F-actin), resulting in impaired bone-resorbing activity by the mature osteoclasts. In addition, micro-computed tomography (µ-CT) analysis of the murine model revealed that DM had a beneficial effect on lipopolysaccharide (LPS)-mediated bone erosion. Histological analysis showed that DM attenuated the degradation of trabecular bone matrix and formation of TRAP-positive osteoclasts in bone tissues. These results suggest that DM is a potential candidate for the treatment of metabolic bone disorders such as osteoporosis.
Subject(s)
Bone Resorption/drug therapy , Dendrobium/chemistry , NFATC Transcription Factors/metabolism , Osteoclasts/cytology , Plant Extracts/administration & dosage , RANK Ligand/metabolism , Animals , Bone Resorption/chemically induced , Bone Resorption/metabolism , Cell Differentiation/drug effects , Cells, Cultured , Disease Models, Animal , Gene Expression Regulation/drug effects , In Vitro Techniques , Lipopolysaccharides/adverse effects , Mice , Osteoclasts/drug effects , Osteoclasts/metabolism , Plant Extracts/pharmacologyABSTRACT
Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.